Abstract 18847: Secretoneurin Provides Independent Prognostic Information in Patients with Heart Failure and Cardiac Arrest, and has a Direct Inhibitory Effect on Diastolic Ca2+ Leak and Arrhythmogenic Ca2+ Waves via CaMKIId Inhibition
Background: Secretoneurin (SN) levels are increased in patients with heart failure (HF), but whether SN provides prognostic information in cardiovascular disease (CVD) and influences cardiomyocyte function are not known.
Methods and Results: Circulating SN was measured <24 h of hospitalization in 134 patients with acute HF and <6 h of hospitalization in 155 patients with ventricular arrhythmias and out-of-hospital cardiac arrest (OHCA-VF). SN levels were associated with mortality in acute HF patients (median follow-up 776 days, 66 deaths) after adjusting for established risk factors, including hs-TnT and NT-proBNP levels: HR [logSN] 4.27 (95% CI 1.83-9.94), p=0.001. SN levels were also associated with short-term mortality after OHCA-VF (30 days, 51 deaths) after adjusting for established risk factors and biomarkers: HR [logSN] 3.33 (1.83-6.05), p<0.001. Perfusing hearts with SN increased myocardial SN levels and SN was internalized into cardiomyocytes via endocytosis. Intracellularly, SN was found to directly bind to calmodulin (CaM) and Ca2+/calmodulin (CaM)-dependent protein kinase II δ (CaMKIIδ). SN attenuated CaMKIIδ activity, reduced CaMKIIδ-dependent ryanodine receptor (RyR) phosphorylation, lowered diastolic Ca2+ leak at different concentrations, and increased sarcoplasmic reticulum Ca2+ content. These results were also consistent with results from cardiomyocytes of HF animals, as SN reduced RyR leak in HF reflected by less Ca2+ sparks and waves. SN also reduced basal and isoproterenol (ISO)-induced frequency and dimensions of Ca2+ sparks and the development of arrhythmogenic Ca2+ waves, attenuated ISO-induced CaMKIIδ autophosphorylation, and reduced CaMKIIδ-induced RyR phosphorylation in the presence of ISO.
Conclusions: SN is a novel CV biomarker that provides independent prognostic information to established risk indices and reduces diastolic Ca2+ leak and arrhythmogenic Ca2+ waves via direct CaMKIIδ inhibition, which identifies high SN levels as a compensatory mechanism in the most severely ill patients.
Author Disclosures: A. Ottesen: None. W. Louch: None. C. Rein Carlson: None. O. Bjarnason Landsverk: None. J. Kurola: None. R. Forstrøm Johansen: None. M. Moe: None. J. Aaronsen: None. A. Høiseth: None. H. Jarstadmarken: None. S. Nygård: None. M. Bjørås: None. I. Sjaastad: None. V. Pettilä: None. M. Stridsberg: Ownership Interest; Modest; SN. T. Omland: Ownership Interest; Modest; SN. G. Christensen: Ownership Interest; Modest; SN. H. Røsjø: Ownership Interest; Modest; SN.
- © 2014 by American Heart Association, Inc.